PrISOFLURANE, USP
Pharmaceutical Partners of Canada Inc. Date of Preparation: 45 Vogell Road, Suite 200 January 14, 2008 Richmond Hill, ON L4B 3P6 Control No. : 119264
Pr ISOFLURANE, USP
Isoflurane, USP (Isoflurane, 99.9%) is an inhalation anesthetic whose low solubility (blood/gas partition coefficient equals 1.4), permits a rapid induction of and recovery from anesthesia. The mild pungency of isoflurane may limit the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. The level of anesthesia may be changed rapidly with isoflurane. Pharyngeal and laryngeal reflexes are readily and easily obtunded. Isoflurane is a profound respiratory depressant. An increase in anesthetic dose will decrease tidal volume without changing respiratory rate. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane. Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia correspondingly decrease blood pressure. Nitrous oxide diminishes the inspired concentration of isoflurane required to reach a desired level of anesthesia and has a favourable effect on the parameters of the anesthetic process. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia primarily through an increase in heart rate which compensates for a reduction in stroke volume. The hypercapnia which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. The cardiac rhythm during isoflurane anesthesia is stable. In dog studies, isoflurane has not been found to sensitize the myocardium to exogenously administered epinephrine. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not cause ventricular arrhythmias in patients anesthetized with isoflurane. Doubling this dose will produce ventricular extrasystoles in about half of patients anesthetized with 1.25 MAC isoflurane. Muscle relaxation usually is adequate for intra-abdominal operations at normal levels of anesthesia. All commonly used muscle relaxants are compatible with isoflurane. Complete paralysis can be attained with small doses of muscle relaxants. Isoflurane potentiates all commonly used muscle relaxants, the effect being most profound with nondepolarizing relaxants. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane but does not reverse the direct neuromuscular depression of isoflurane. The metabolism of isoflurane is low in miniature swine, black C-57 mice, and Fischer 344 rats. Less than half of one percent of the isoflurane taken up in humans can be recovered as metabolites.
Isoflurane, USP (Isoflurane, 99.9%) may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.
Known sensitivity to Isoflurane, USP (Isoflurane, 99.9%) or to other halogenated agents.
Levels of anesthesia may be altered easily and rapidly; therefore, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory depression increase as anesthesia is deepened.
Therefore, less than the usual amounts of such agents should be used. Neostigmine reverses the effects of nondepolarizing muscle relaxants, but does not reverse the direct neuromuscular depression of isoflurane.
Blood loss during abortion is increased when halogenated agents such as isoflurane are used for anesthesia. Isoflurane may increase cerebral blood flow and hence cerebrospinal fluid pressure, and therefore should be used with special care in patients with pre-existing increases in cerebrospinal fluid pressure. This effect on flow and pressure is reversed by hyperventilation. The safety of repeated anesthesia with isoflurane has not been established.
Use in Pregnancy
The safety of isoflurane anesthesia to mother and fetus has not been established. Reproduction studies in rats and mice reveal no evidence of harm to the fetus. The relevance of these studies to the human is not known. There are no data on the use of isoflurane in pregnant women.
BSP (Bromsulfalein) retention is mildly elevated postoperatively in some cases. There is some elevation of glucose and white blood count intraoperatively. Glucose elevation should be considered in diabetic patients.
Malignant Hyperthermia
In susceptible individuals, Isoflurane, USP (Isoflurane, 99.9%) anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid- acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.
Hypotension, respiratory depression, arrhythmias, shivering, nausea, vomiting, and postoperative ileus have been reported. As with all other anesthetics, elevation of the white blood count has been observed following anesthesia even in the absence of surgical stress. Elevation of SGOT, LDH, alkaline phosphatase and bilirubin with or without frank jaundice, have been reported in the postoperative period following Isoflurane, USP anesthesia in some patients. The relationship to isoflurane has not been clarified. Delirium, hallucinations and hiccup occur rarely.
Overdosage with Isoflurane, USP (Isoflurane, 99.9%) produces marked hypotension and may cause apnea. In the event of overdosage, or what appears to be overdosage, the following should be done:
Stop drug administration.
Establish that the airway is clear.
Instigate assisted or controlled ventilation with pure oxygen as the circumstances dictate.
Preanesthetic Medication
Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by Isoflurane, USP (Isoflurane, 99.9%) and that the heart rate tends to be increased. The use of anticholinergic drugs is a matter of choice.
Induction
Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath-holding, or laryngospasm. These difficulties may be avoided by use of a hypnotic dose of a short-acting barbiturate preceding the isoflurane mixture. Inspired concentrations of 1.5 to 3.0% isoflurane with a background of 50 to 70% nitrous oxide usually produce surgical anesthesia in 7 to 10 minutes. If nitrous oxide is not used, an additional 1.0 to 1.5% isoflurane may be required for induction of anesthesia.
Maintenance
Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when 50 to 70% nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when isoflurane is given in oxygen alone. Additional relaxation may be produced with supplemental doses of muscle relaxants. In the absence of other complicating problems, blood pressure during maintenance varies inversely with isoflurane concentration. Excessive decreases may be due to depth of anesthesia and in such instances may be corrected by lightening anesthesia. MAC (minimum alveolar concentration) in man:
| Age | With 100% Oxygen | With 70% N 2 O |
| 26 +- 4 | 1.28% | 0.56% |
| 44 +- 7 | 1.15% | 0.50% |
| 64 +- 5 | 1.05% | 0.37% |
Administration Equipment
The delivered concentration of Isoflurane, USP should be known. Isoflurane may be vaporized from a flow-through vaporizer specifically calibrated for isoflurane. Vaporizers which deliver saturated vapour at reasonable flows but are not specifically calibrated for isoflurane may be used. The delivered concentration from such a vaporizer may be calculated using the formula: % Isoflurane = 100 PV FV FT (PA - PV)
| P A | = | Pressure of atmosphere |
| P V | = | Vapour pressure of isoflurane |
| F V | = | Flow of gas through vaporizer (mL/min) |
| F T | = | Total flow gas used (mL/min) |
Isoflurane contains no stabilizer and vaporization of isoflurane does not leave a residual material which might alter the calibration operation of a vaporizer.
To attach a keyed bottle adaptor, remove cap and seal from anesthetic bottle.
Check that the anesthetic bottle neck is not chipped or damaged.
Match keyed bottle adaptor to keyed bottle collar and screw together until tight.
Now connect the bottle to the vaporizer filler receptable.
Drug Substance
Isoflurane, USP
Isoflurane, USP is a halogenated methyl ethyl ether with the chemical name 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether.
Molecular Formula: C3H2ClF5O
184.50
Isoflurane is a clear, colourless liquid having a slight odour. It is nonflammable and soda lime stable. Easily miscible with organic liquids including fats and oils. Insoluble in water. Boiling point is 48.5degC (uncorrected).
Boiling point (at 760 mm Hg):
48.5degC
1.2990 - 1.3005
| Specific gravity 25deg/25degC: Vapour pressure in mm Hg: | 1.496 18degC | 218 |
| 20degC | 238 | |
| 22degC | 261 | |
| 24degC | 285 | |
| 26degC | 311 |
| log 10 P vap | = | A + B | A | = | 8.056 |
| T | B T | = = | -1664.58 degC + 273.16 (Kelvin) |
| Water/gas | 0.61 |
| Blood/gas | 1.43 |
| Oil/gas | 90.8 |
Isoflurane, USP (Isoflurane, 99.9%) is packaged in 100 and 250 mL amber-coloured bottles.
Isoflurane produces general anesthesia on inhalation in mice, dogs, monkeys, rabbits, and rats. The low blood/gas partition coefficient (1.4 for isoflurane compared to 1.9 for enflurane and 2.4 for halothane) permits a rapid induction of and recovery from anesthesia. Recovery is free from nausea, vomiting, or evidence of malaise. MAC in dogs, the minimum alveolar concentration at which 50% of the animals move in response to pain stimulation, is 1.46%. The anesthetic index in dogs (dose at apnea divided by MAC) is 2.5. The anesthetic index for other anesthetics is: enflurane 2.0, halothane 2.9, cyclopropane 2.4, and diethyl ether 2.9. In rats, isoflurane is favoured in either of two anesthetic indices indicating margin of safety (see
). The respiratory anesthetic index is the ratio of the brain
anesthetic concentration at respiratory arrest/minimum brain anesthetic concentration producing anesthesia. The cardiac arrest index is the ratio of the myocardial anesthetic concentration at circulatory collapse/minimum heart anesthetic concentration at which anesthesia is produced.
TABLE: Anesthetic Indices | ||
|---|---|---|
| Respiratory | Cardiac | |
| Isoflurane | 3.1 | 5.7 |
| Halothane | 2.3 | 3.0 |
| Methoxyflurane | 2.2 | 3.7 |
| Enflurane | 1.8 | 3.3 |
Like other halogenated agents, isoflurane causes respiratory depression and respiratory acidosis in dogs, rats, rabbits, monkeys, and humans. The arrhythmic doses of epinephrine in dogs anesthetized with isoflurane or fluroxene do not differ from those which produce arrhythmias in the awake animal. Significantly lower doses are found for halothane anesthetized animals. Similarly, the dose of epinephrine producing ventricular extrasystoles in 50 percent of humans anesthetized with 1.25 MAC isoflurane is 6.7 ug per kg when the epinephrine is injected submucosally. This would equal 47 mL of a 1:100,000 epinephrine containing solution in a 70 kg man. Isoflurane does not cause EEG spiking or convulsive activity either at high, normal or low levels of arterial PCO2. Twitching or other muscular movement suggesting increased central nervous system hyperactivity is not provoked by isoflurane.
Metabolism
Several metabolic studies were conducted in both animals and man. In Fischer 344 rats, the peaks of inorganic fluoride ion occurred during the second 24 hours postanesthesia; all values had returned to baseline 2 to 3 days later (organic fluoride to inorganic fluoride ratio 0:53:1). Pretreatment with phenobarbital did not change the fluoride values. Also in mice and rats, little or no skeletal deposition of fluoride ions did occur, suggesting low or no metabolism for Isoflurane, USP (Isoflurane, 99.9%). In miniature swine treated with subanesthetic doses, values indicated little or no metabolism of isoflurane.
In vitro
studies confirmed the findings using livers from both untreated and phenobarbital pretreated mice and rats. When the liver homogenates were exposed to isoflurane, inorganic fluoride production was very low.
In three human volunteers given 0.9% (0.8 MAC) of isoflurane for an average of 2.8 hours, it was also found that the metabolism of isoflurane was low. The peaks occurred during the first postanesthetic day; by the third day all values had returned to preanesthetic levels. Tonic fluoride levels in urine rose from around 100 uM/day preanesthesia to a peak of around 400 uM and had returned to baseline levels on the fourth postanesthetic day.
Acute
A single acute study in 4 week old female mice given Isoflurane, USP (Isoflurane, 99.9%) intraperitoneally in olive oil yielded an LD50 of 6.74 g/kg (5.87 to 7.77). The animals showed disorientation and hypnosis; at the higher doses some showed convulsions.
Subacute and Chronic
Groups of five mature beagle dogs were exposed to 1.5 MAC of isoflurane, enflurane, halothane, methoxyflurane, nitrous oxide, thiopental. There was a control group of five animals. Each group was exposed for four hours per day every other day, for a total of 16 hours of anesthesia. Histopathological examination of liver and kidney tissues showed no cellular damage related to the anesthetics. Serum creatinine, BUN and SGPT were normal. Urine lysozyme measurements revealed no consistent change in the lysozyme excretion, with no differences among the anesthetics. It was concluded from these results that there was no renal or hepatic toxic effect from isoflurane or any other anesthetic. Five groups of five Rhesus monkeys were exposed for four hours per day on alternate days for a total of 16 hours of anesthesia. The anesthetic agents used were isoflurane (1.5 to 2.5%), enflurane (1.5 to 2.0%), methoxyflurane (0.5 to 0.7%), and halothane (1.0 to 1.25%). No other drugs were administered. No significant changes in serum creatinine, BUN or SGPT were found. The minimal changes found in liver and kidney tissues did not indicate that isoflurane was nephrotoxic or hepatotoxic. The chronic toxicity of isoflurane was compared to that of halothane and diethyl ether in mice, rats, and guinea pigs. Animals were exposed continuously for 35 days to 0.05% or 1/30th MAC isoflurane. At the end of this period, all species showed no effect other than a slightly lower weight gain compared to controls. By comparison, halothane animals tolerated only 1/200th MAC, or 0.005% concentration. At concentrations higher than this, halothane exhibited focal hepatic necrosis and lipoidosis which was not seen in the animals exposed to isoflurane. Human volunteers given isoflurane at 1 to 2 MAC for 6 to 7.5 hours did not show postanesthetic evidence of significant liver or renal impairment. BSP retention was slightly increased 24 hours following anesthesia although the values remained in the normal range. This result differed from the result obtained in similar tests with halothane or fluroxene; the latter agents increased BSP significantly above normal. Isoflurane did not significantly affect SGOT, SGPT or LDH. Isoflurane did not increase BUN or serum creatinine. A 15 month chronic toxicity study was also carried out in Swiss ICR mice. Isoflurane, enflurane, halothane, methoxyflurane and nitrous oxide were used; air and oxygen were given to groups of control mice. The anesthetics were given at 1/2, 1/8 and 1/32 MAC for four exposures to the mothers during pregnancy, and for 24 exposures to the pups postpartum. The pups were followed to 15 months, at which time they were sacrificed and autopsied. No significant differences were found between isoflurane-treated animals and those exposed to halothane, enflurane, methoxyflurane or nitrous oxide.
Reproduction studies, including fertility, general reproductive performance, embryotoxicity, teratogenicity, and lactation, did not show any abnormality in mice and rats using Isoflurane, USP (Isoflurane, 99.9%) at 0.1 to 0.6%.
Stevens WC, Dolan WM, Gibbons RT, White A, Eger EI II, Miller RD, Dejong RH, and Elashoff RM: Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 42(2): 197-200, 1975.
Dobkin AB, Byles PH, Ghanooni S, and Valbuena DA: Clinical and laboratory evaluation of a new inhalation anaesthetic, Forane(r) (Compound 469) CHF2-O-CHCICF3. Canad. Anaesth. Soc. J. 18 (3): 264-271, 1971.
Homi J, Eckenhoff JE, Konchigeri HN, and Linde HW: A new anesthetic - Forane(r): Preliminary observations in man. Anesth. And Analg. 51(3) 439-447, 1972.
Pauca AL and Dripps RD: Clinical experience with isoflurane (Forane(r)): Preliminary communication. Br. J. Anaesth. 45: 697-703, 1973.
Joas TA and Stevens WC: Comparison of the arrhythmic doses of epinephrine during Forane(r), halothane and fluroxene anesthesia in dogs. Anesthesiology 35(1): 48-53, 1971.
Johnston RR, Eger EI II, and Wilson C: A comparative interaction of epinephrine with enflurane, isoflurane, and halothane in man. Anesth. And Analg. 55(5): 709-712, 1976.
Halsey MJ, Sawyer DC, Eger EI II, Bahlman SH, and Impelman DMK: Hepatic metabolism of halothane, methoxyflurane, cyclopropane, Ethrane(r), and Forane(r) in miniature swine. Anesthesiology 35(1): 43-47, 1971.
Fiserova-Bergerova V: Changes of fluoride content in bone: An index of drug defluorination in vivo. Anesthesiology 38(4): 345-351, 1973.
Cousins MJ, Mazze RI, Barr GA, and Kosek JC: A comparison of the renal effects of isoflurane and methoxyflurane in Fischer 344 rats. Anesthesiology 38(6):557-563, 1973.
Stevens WC, Eger EI II, White A, Halsey MJ, Munger W, Gibbons RD, Dolan W, and Shargel R: Comparative toxicities of halothane, isoflurane and diethyl ether at subanesthetic concentrations in laboratory animals. Anesthesiology 42(4): 408-419, 1975.
Byles PH, Dobkin AB, and Jones DB: Forane(r) (Compound 469): 3. Comparative effects of prolonged anesthesia on mature beagle dogs and young Rhesus monkeys. Canada. Anaesth. Soc. J. 18(4): 397-407, 1971.
Eger EI II, White AE, Brown CL, Biava CG, Corbett TH, and Stevens WC: A test of the carcinogenicity of enflurane, isoflurane, halothane, methoxyflurane, and nitrous oxide in mice. Anesth. And Analg. 57: 678-694, 1978.
BIBLIOGRAPHY (continued)
Holaday DA, Fiserova-Bergerova V, Latto IP et al. : Resistance of isoflurane to biotransformation in man. Anesthesiology 43: 325-332, 1975. Stevens WC, Eger EI II, Joas TA, et al. : Comparative toxicity of isoflurane, halothane, fluroxene, and diethyl ether in human volunteers. Canad. Anaesth. Soc. J. 20: 357-368, 1973. Wolfson B, Hetrick WD, Lake CL, and Siker ES: Anesthetic indices - further data. Anesthesiology 48: 187-190, 1978.